title: No evidence exists for methylation inactivation of the p16 tumor suppressor gene in ovarian carcinogenesis.
abstract: The p16ink4/CDKN2/MTS1 tumor suppressor gene encodes a cyclin-dependent kinase inhibitor which plays an important role in regulation of the G1/S phase cell cycle checkpoint. Loss of heterozygosity (LOH) at the p16 locus, 9p21, has been documented in a wide variety of tumors including ovarian carcinoma. However, inactivating mutations of the remaining allele and homozygous deletions are relatively infrequent events in primary tumors, even in cases where expression of p16 at the mRNA and protein level is clearly absent. These findings initially cast doubt on the role of p16 as a tumor suppressor gene in vivo. Recently, an alternative mechanism of p16 inactivation involving methylation of the CpG island in the 5' region of the gene has been demonstrated in a number of malignancies and cell lines. In this study we have analyzed the methylation status of four CpG dinucleotides in a panel of 23 ovarian tumors using a multiplex PCR approach to correlate our findings with the LOH data in this region. Using the microsatellite markers D9S171 and D9S1679 LOH was demonstrated in 4/22 (18%) informative cases. All 23 tumors showed no evidence of methylation at the p16 locus including the 4 tumors demonstrating LOH at 9p21. These results suggest that methylation inactivation of the p16 gene does not play an important role in ovarian carcinogenesis.
authors.affiliation: Gynaecology Cancer Research Unit, St. Bartholomew's Hospital, West Smithfield, London, England, EC1A 7BE, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Ryan
authors.forename: R M
authors.initials: RM
authors.lastname: Al-Jehani
authors.forename: K T
authors.initials: KT
authors.lastname: Mulligan
authors.forename: I J
authors.initials: IJ
authors.lastname: Jacobs
mesh_terms: D000483:Alleles; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D002899:Chromosomes, Human, Pair 9; D019175:DNA Methylation; D017931:DNA Primers / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D004276:DNA, Satellite / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D019942:Genes, p16 / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; D004273:DNA, Neoplasm; D004276:DNA, Satellite